Methylation-associated silencing of the Thrombospondin-1 gene in human neuroblastoma

Qi Wei Yang, Shuqing Liu, Yufeng Tian, Helen R. Salwen, Alexandre Chlenski, Joanna Weinstein, Susan L. Cohn

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Abstract

Tumor angiogenesis, a major requirement for tumor outgrowth and metastasis, is regulated by pro- and antiangiogenic factors. Methylation-associated inactivation of the angiogenesis inhibitor thrombospondin-1 (TSP-1) has been observed recently in some adult tumors. To investigate the role of TSP-1 in pediatric cancer, we examined its pattern of expression and mechanisms of regulation in neuroblastoma (NB). TSP-1 was silenced in a subset of undifferentiated, advanced-stage tumors and NB cell lines. In contrast, most localized tumors expressed this angiogenesis inhibitor, and a significant correlation between morphological evidence of neuroblast differentiation and TSP-1 expression was observed. Luciferase assays demonstrated the presence of nuclear factors required for TSP-1 transcription in both TSP-1-positive and -negative cell lines, but no correlation between TSP-1 promoter activity and the level of TSP-1 mRNA expression was seen. Our studies indicate that the transcriptional silencing of TSP-1 was caused by methylation. TSP-1 promoter methylation was detected in all of the NB cell lines lacking TSP-1 mRNA and in 37% of the NB clinical tumors analyzed. Furthermore, treatment with the demethylating agent, 5-Aza-2′-deoxycytidine (5-Aza-dC), restored TSP-1 expression in NB cell lines. Disrupting methylation with 5-Aza-dC also led to significant inhibition of NB in vivo and re-expression of TSP-1 in a subset of NB xenografts. These results suggest that 5-Aza-dC inhibits NB growth by augmenting the expression of TSP-1 along with other genes that suppress tumor growth. Demethylating agents may prove to be effective candidates for the treatment of children with NB.

Original languageEnglish (US)
Pages (from-to)6299-6310
Number of pages12
JournalCancer Research
Volume63
Issue number19
StatePublished - Oct 1 2003

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yang, Q. W., Liu, S., Tian, Y., Salwen, H. R., Chlenski, A., Weinstein, J., & Cohn, S. L. (2003). Methylation-associated silencing of the Thrombospondin-1 gene in human neuroblastoma. Cancer Research, 63(19), 6299-6310.